Tadpoles can achieve something that humans may only dream of: pull off a tadpole's thick tail or a tiny developing leg, and
it'll grow right back — spinal cord, muscles, blood vessels and all. Now researchers have discovered the key regulator of
the electrical signal that convinces Xenopus pollywogs to regenerate amputated tails. The results, reported this week in Development, give some researchers hope for new approaches to stimulating tissue regeneration in humans1.

Researchers have known for decades that an electrical current is created at the site of regenerating limbs. Furthermore, applying
an external current speeds up the regeneration process, and drugs that block the current prevent regeneration. The electrical
signals help to tell cells what type to grow into, how fast to grow, and where to position themselves in the new limb.

To investigate, Michael Levin and his colleagues at the Forsyth Center for Regenerative and Developmental Biology in Boston,
Massachusetts, sorted through libraries of drug compounds to find ones that prevent tail regeneration but do not interfere
with wound healing. One such drug, they found, blocks a molecular pump that transports protons across cell membranes; this
kind of proton flow creates a current.

Levin speculates that the current generated by this proton pump produces a long-range electric field that helps to direct
what happens to nerve cells pouring into the site. "We can use this hydrogen pumping as a top-level master control to initiate
the regeneration response," says Levin. "We didn't have to specifically say, 'put a little muscle over here, a little muscle
over there'."

The proton pump could also be used to turn on limb regeneration in older tadpoles that would normally have lost this ability.
When Levin and his colleagues activated the proton pump during this older phase, tadpoles were more than four times more likely
to regrow a perfectly formed tail than their normal counterparts.

Chop and change

“Many children under the age of seven have regrown amputated fingertips.

The notion of regenerating complex organs from adult cells hasn't always been popular, says David Stocum, director of the
Indiana University Center for Regenerative Biology and Medicine in Indianapolis. "People used to pooh-pooh the idea," says
Stocum, "but now there's renewed interest in it." That interest has been primarily focused on the regenerative power of stem
cells. But there is also some interest in direct regeneration from adult cells at the wound site.

At first glance, dramatic limb and tail regenerations seem to be restricted to 'simpler' creatures, such as the humble planaria
flatworm — chop it up into a hundred pieces and you'll soon have a hundred little worms on your hands — and salamanders, which
can grow back limbs, tails, jaws, intestines and some parts of their eyes and hearts.

But there are impressive examples of tissue regeneration in mammals as well. Male deer can grow the bone, skin, nerves and
blood vessels of their antlers at a millimetre a day. Humans can regenerate livers, and many children under the age of seven
have regrown amputated fingertips. And then there are the odd medical journal case studies of patients who have lost, say,
a kidney, only to find years later that they've sprouted a new one.

Simple switch

Changes in electrical current have been measured in regenerating fingertips, just as in a tadpole's regenerating tail. But
converting humans into fully functioning regenerators will probably take more than directing bioelectrical signals. The formation
of scar tissue, for example, could inhibit regeneration in some cases, says David Gardiner, a biologist at the University
of California, Irvine.

But the complex networks needed to construct a complicated organ or appendage are already genetically encoded in all of our
cells — we needed them to develop those organs in the first place. "The question is: how do you turn them back on?" Levin
says. "When you know the language that these cells use to tell each other what to do, you're a short step away from getting
them to do that after an injury."

The simplicity of the regeneration start signal is promising, says Stocum: it is just possible that a properly tuned electric
signal is all humans need to jumpstart tissue regeneration.